CN115279769A - Crystalline forms of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-D ] pyrimidin-6-yl) phenyl) -N' -methoxyurea - Google Patents
Crystalline forms of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-D ] pyrimidin-6-yl) phenyl) -N' -methoxyurea Download PDFInfo
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- CN115279769A CN115279769A CN202080084633.9A CN202080084633A CN115279769A CN 115279769 A CN115279769 A CN 115279769A CN 202080084633 A CN202080084633 A CN 202080084633A CN 115279769 A CN115279769 A CN 115279769A
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Abstract
The present disclosure relates to N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]A crystalline form of pyrimidin-6-yl) phenyl) -N' -methoxyurea, particularly form II. The disclosure also relates to a method forProcesses for preparing said crystalline forms and pharmaceutical compositions containing them.
Description
Cross Reference to Related Applications
This application is a continuation of U.S. patent application serial No. 62/913,560 filed on 10/2019, the entire disclosure of which is incorporated herein by reference in its entirety.
The present disclosure relates to novel crystalline forms of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, also referred to herein as compound 1. The disclosure also relates to methods of making the disclosed crystalline forms, pharmaceutical compositions and kits comprising them, and methods of treatment and uses comprising their administration.
Background
Compound 1: n- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea is a gonadotropin releasing hormone (GnRH) antagonist, being developed as a new agent, useful in the treatment of a variety of conditions, including menstrual bleeding and other symptoms associated with uterine leiomyoma, pain and other symptoms associated with endometriosis, and prostate cancer. Compound 1 may also be useful for treating other diseases or disorders. See, e.g., U.S. Pat. No. 7,300,935, U.S. Pat. No. 8,058,280, U.S. Pat. No. 8,735,401, U.S. Pat. No. 9,346,822, WO2018060501, and WO2018060463.
U.S. patent No. 9,758,528, which is incorporated herein by reference in its entirety, describes a method for producing compound 1 and certain synthetic intermediates as well as two crystalline forms of compound 1: a crystal of tetrahydrofuran solvate of compound 1 and a crystal of an anhydrous form of compound 1 (referred to herein as form I of compound 1). For reference, as detailed in U.S. patent No. 9,758,528, form I of compound 1 may be characterized by an XRPD pattern having peaks at approximately 7.4 °, 8.9 °, 9.9 °, 12.1 °, 16.6 °, 17.3 °, 22.2 °, 22.8 °, and 27.4 ° 2 θ.
Form I of compound 1 may also be characterized by the XRPD pattern depicted in fig. 25 of the present application. Form I of compound 1 starts to melt at about 189 ℃ and starts to degrade at about 197 ℃. Form I of compound 1 showed an exothermic peak at about 237 ℃ according to DSC and degradation at about 245 ℃ according to TG. Fig. 28 and 29 show the thermogravimetric analysis (TG) and Differential Scanning Calorimetry (DSC) thermograms, respectively, of form I of compound 1.
Disclosure of Invention
One aspect of the present disclosure relates to one crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, which is referred to as form II of compound 1. In some embodiments, form II of compound 1 is characterized by an X-ray powder diffraction (power diffraction) pattern comprising at least three peaks selected from 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, form II of compound 1 is characterized by an X-ray powder diffraction pattern comprising at least five peaks selected from 7.2 °, 9.7 °, 10.7 °, 13.1 °, 15.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, form II of compound 1 is characterized by an X-ray powder diffraction pattern comprising peaks at 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ. In certain such embodiments, the X-ray powder diffraction pattern comprises one or more peaks selected from 7.2 °, 13.1 °, and 15.7 ° ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern of form II of compound 1 is substantially the same as the pattern shown in figure 1.
In some embodiments, form II of compound 1 is characterized by an onset of degradation between about 174 ℃ to about 176 ℃. In some embodiments, form II of compound 1 is characterized by beginning degradation at about 175 ℃. In some embodiments, form II of compound 1 is characterized by a thermogravimetric analysis (TG) thermogram substantially the same as the pattern shown in figure 2.
In some embodiments, form II of compound 1 is characterized by an onset of melting between about 179 ℃ to about 181 ℃. In some embodiments, form II of compound 1 is characterized by an onset of melting at about 180 ℃. In some embodiments, form II of compound 1 is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an exothermic peak between about 191 ℃ to about 194 ℃. In some embodiments, form II of compound 1 is characterized by a DSC thermogram comprising an exothermic peak at about 192 ℃. In some embodiments, form II of compound 1 is characterized by a DSC thermogram substantially the same as the one set forth in figure 3.
In some embodiments, form II of compound 1 is characterized by having at least two of:
a) The XRPD pattern comprises at least three peaks selected from 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ;
b) Degradation started at about 175 ℃ as measured by TG; and
c) As measured by DSC, has an exothermic peak at about 192 ℃.
One aspect of the present disclosure relates to a pharmaceutical composition comprising a crystalline form of the present disclosure and a pharmaceutically acceptable carrier.
Another aspect of the present disclosure relates to a process for preparing form II of compound 1, comprising:
a) Dissolving a crystalline form of form I N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, referred to as compound 1, in a mixture of DMF and acetone (about 6, 94, v/v) at about 25 ℃ to form a solution;
b) Stirring the solution at a temperature of about-15 ℃ to about-25 ℃ for about 3 days to produce a suspension; and
c) The solid was isolated from the suspension by vacuum filtration to provide form II of compound 1.
The method can include vacuum drying the isolated solid at about 60 ℃ for about 4 hours to provide form II of compound 1.
Drawings
Figure 1 depicts the powder X-ray diffraction pattern of form II of compound 1.
Figure 2 depicts the thermogravimetric analysis (TG) thermogram of form II of compound 1.
Figure 3 depicts a Differential Scanning Calorimetry (DSC) thermogram for form II of compound 1.
Figure 4 depicts the powder X-ray diffraction pattern of form III of compound 1.
Figure 5 depicts the TG thermogram of form III of compound 1.
Figure 6 depicts the DSC thermogram of form III of compound 1.
Figure 7 depicts the powder X-ray diffraction pattern of form V of compound 1.
Fig. 8 depicts the TG thermogram of form V of compound 1.
Figure 9 depicts the DSC thermogram for form V of compound 1.
Figure 10 depicts a powder X-ray diffraction pattern of form VI of compound 1.
Fig. 11 depicts the TG thermogram of form VI of compound 1.
Figure 12 depicts a DSC thermogram for form VI of compound 1.
Figure 13 depicts a powder X-ray diffraction pattern of form VII of compound 1.
Fig. 14 depicts the TG thermogram of form VII of compound 1.
Figure 15 depicts a DSC thermogram for form VII of compound 1.
Figure 16 depicts the powder X-ray diffraction pattern of form VIII of compound 1.
Fig. 17 depicts the TG thermogram of form VIII of compound 1.
Figure 18 depicts a DSC thermogram for form VIII of compound 1.
Figure 19 depicts a powder X-ray diffraction pattern of form IX of compound 1.
Fig. 20 depicts a TG thermogram of form IX of compound 1.
Figure 21 depicts a DSC thermogram for form IX of compound 1.
Figure 22 depicts a powder X-ray diffraction pattern of form X of compound 1.
Fig. 23 depicts the TG thermogram of form X of compound 1.
Figure 24 depicts a DSC thermogram for form X of compound 1.
Figure 25 depicts the powder X-ray diffraction pattern of form I of compound 1. Modified from figure 2 of us patent No. 9,758,528.
Figure 26 depicts a powder X-ray diffraction pattern of crystals of tetrahydrofuran solvate of compound 1. Modified from figure 1 of us patent No. 9,758,528.
Figure 27 depicts the conversion of forms II, III and IV to form I. (1) Competitive slurries in EtOH at 25 ℃ and 40 ℃ and EtOAc at 5 ℃, 25 ℃ and 40 ℃. (2) And (4) heating. (3) And (4) heating. (4) Under room temperature and normal humidity conditions.
Fig. 28 depicts the TG thermogram of form I of compound 1.
Figure 29 depicts a DSC thermogram for form I of compound 1.
Figure 30 depicts a powder X-ray diffraction pattern of form XI of compound 1.
Fig. 31 depicts the TG thermogram (upper panel) and DSC thermogram (lower panel) of form XI of compound 1.
Figure 32 depicts a powder X-ray diffraction pattern of form XII of compound 1.
Fig. 33 depicts the TG thermogram (upper panel) and DSC thermogram (lower panel) of form XII of compound 1.
Detailed Description
Described herein are novel crystalline forms of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea (compound 1), methods of making them, pharmaceutical compositions and kits comprising them, and methods of treatment and uses comprising their administration. The chemical structure of compound 1 is as follows:
general information
The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" refers to one element or more than one element.
In this disclosure, the term "and/or" is used to mean "and" or "unless otherwise indicated.
Crystalline forms of the present disclosure
Table 1 lists various crystalline forms described herein. As used herein, the term "solvate" includes stoichiometric and non-stoichiometric solvates, such as channel-type solvates, formed from compound 1 and a solvent. Examples of suitable solvents may include, but are not limited to, water, toluene, THF, anisole, isopropanol, dioxane, α, α, α -trifluorotoluene, and trifluoroethanol. Solvates in which water is the solvent molecule are commonly referred to as hydrates. Hydrates can include compositions containing a stoichiometric amount of water as well as compositions containing variable amounts of water. As will be appreciated by the skilled artisan, unlike stoichiometric hydrates, dehydration and rehydration of non-stoichiometric hydrates is not accompanied by a phase change and therefore all hydration states generally represent the same crystalline form.
Form II of Compound 1
The present disclosure provides a crystalline form of compound 1, referred to as form II of compound 1. In some embodiments, form II of compound 1 is an anhydrate. In some embodiments, form II of compound 1 is characterized by an XRPD pattern comprising at least three peaks selected from 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, form II of compound 1 is characterized by an XRPD pattern comprising at least five peaks selected from 7.2 °, 9.7 °, 10.7 °, 13.1 °, 15.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, form II of compound 1 is characterized by an XRPD pattern having peaks at 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 θ ± 0.2 ° 2 θ. In certain such embodiments, the XRPD pattern has one or more peaks selected from 7.2 °, 13.1 °, and 15.7 ° ± 0.2 ° 2 Θ. In some embodiments, form II of compound 1 is characterized by an XRPD pattern substantially the same as the pattern shown in figure 1.
Form II of compound 1 can also be characterized using thermogravimetric analysis (TG). In some embodiments, form II of compound 1 is characterized by an onset of degradation between about 174 ℃ to about 176 ℃. In some embodiments, form II of compound 1 is characterized by beginning degradation at about 175 ℃. In some embodiments, form II of compound 1 is characterized by a TG thermogram substantially the same as the pattern shown in fig. 2.
Form II of compound 1 can also be characterized using Differential Scanning Calorimetry (DSC). In some embodiments, form II of compound 1 is characterized by an onset of melting between about 179 ℃ to about 181 ℃ and/or an exothermic peak between about 191 ℃ to about 194 ℃. In some embodiments, form II of compound 1 is characterized by an onset of melting at about 180 ℃ and/or an exothermic peak at about 192 ℃. In some embodiments, form II of compound 1 is characterized by a DSC thermogram substantially the same as the one set forth in figure 3.
In some embodiments, form II of compound 1 is characterized by having at least two of the following:
a) The XRPD pattern comprises at least three peaks selected from 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ;
b) Degradation started at about 175 ℃ as measured by TG; and
c) As measured by DSC, has an exothermic peak at about 192 ℃.
In some embodiments, the XRPD pattern comprises peaks at 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 9.7 °, 10.7 °, and 19.0 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 9.7 °, 10.7 °, and 19.3 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 9.7 °, 10.7 °, and 20.9 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 10.7 °, 19.0 °, and 19.3 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 10.7 °, 19.0 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 10.7 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 19.0 °, 19.3 °, and 20.9 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 9.7 °, 19.0 °, and 19.3 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 9.7 °, 19.0 °, and 20.9 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 9.7 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises one or more peaks selected from 7.2 °, 13.1 °, and 15.7 ° ± 0.2 ° 2 Θ.
Form III of Compound 1
The present disclosure provides a crystalline form of compound 1, referred to as form III of compound 1. In some embodiments, form III of compound 1 is a hemihydrate. In some embodiments, form III of compound 1 is characterized by an XRPD pattern comprising at least three peaks selected from 7.5 °, 9.5 °, 16.8 °, and 18.1 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, form III of compound 1 is characterized by an XRPD pattern comprising at least five peaks selected from 7.5 °, 9.5 °, 12.2 °, 16.6 °, 16.8 °, and 18.1 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, form III of compound 1 is characterized by an XRPD pattern having peaks at 7.5 °, 9.5 °, 16.8 °, and 18.1 ° 2 Θ ± 0.2 ° 2 Θ. In certain such embodiments, the XRPD pattern has one or more peaks selected from 12.2 ° and 16.6 ° ± 0.2 ° 2 Θ. In some embodiments, form III of compound 1 is characterized by an XRPD pattern substantially the same as the pattern shown in figure 4.
Form III of compound 1 can also be characterized using thermogravimetric analysis (TG). In some embodiments, form III of compound 1 is characterized by starting dehydration at about 43 ℃ and continuing dehydration to about 78 ℃. In some embodiments, form III of compound 1 is characterized by an onset of degradation at about 183 ℃. In some embodiments, form III of compound 1 is characterized by a TG thermogram substantially the same as the pattern shown in fig. 5.
Form III of compound 1 can also be characterized using Differential Scanning Calorimetry (DSC). In some embodiments, form III of compound 1 is characterized by an endothermic peak at about 79 ℃ or an exothermic peak at about 205 ℃. In some embodiments, form II of compound 1 is characterized by a DSC thermogram substantially the same as the one set forth in figure 6.
In some embodiments, form III of compound 1 is characterized by having at least two of:
a) The XRPD pattern comprises at least three peaks selected from 7.5 °, 9.5 °, 16.8 °, and 18.1 ° 2 Θ ± 0.2 ° 2 Θ;
b) Dehydration started at about 43 ℃ as measured by TG; and
c) Has an endothermic peak at about 79 ℃ as measured by DSC.
In some embodiments, the XRPD pattern comprises peaks at 7.5 °, 9.5 °, 16.8 °, and 18.1 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 7.5 °, 9.5 °, and 16.8 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 7.5 °, 9.5 °, and 18.1 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 9.5 °, 16.8 °, and 18.1 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 7.5 °, 16.8 °, and 18.1 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises one or more peaks selected from 12.2 ° and 16.6 ° ± 0.2 ° 2 Θ.
Form IV of Compound 1
The present disclosure provides a crystalline form of compound 1, referred to as form IV of compound 1. Form IV, which is considered to be an anhydrous crystalline form other than the other forms disclosed herein, is produced by starting to heat form III at about 52 ℃. After cooling to room temperature, form IV is converted back to form III. Form IV could not be isolated for further characterization.
Form V of Compound 1
The present disclosure provides a crystalline form of compound 1, designated form V of compound 1. In some embodiments, form V of compound 1 is a toluene solvate. In some embodiments, form V of compound 1 is characterized by an XRPD pattern comprising at least three peaks selected from 7.1 °, 10.6 °, 11.2 °, 15.3 °, and 16.7 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, form V of compound 1 is characterized by an XRPD pattern substantially the same as the pattern shown in figure 7.
Form V of compound 1 can also be characterized using TG or DSC. In some embodiments, form V of compound 1 is characterized by a TG thermogram substantially the same as the pattern shown in fig. 8 and/or a DSC thermogram substantially the same as the pattern shown in fig. 9.
In some embodiments, form V of compound 1 is characterized as having at least two of the following:
a) The XRPD pattern comprises at least three peaks selected from 7.1 °, 10.6 °, 11.2 °, 15.3 °, and 16.7 ° 2 Θ ± 0.2 ° 2 Θ;
b) The TG thermogram was substantially the same as the pattern shown in fig. 8; and
c) The DSC thermogram is substantially the same as the pattern shown in figure 9.
In some embodiments, the XRPD pattern comprises peaks at 7.1 °, 10.6 °, 11.2 °, 15.3 °, and 16.7 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 7.1 °, 10.6 °, and 11.2 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 7.1 °, 10.6 °, and 15.3 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 7.1 °, 10.6 °, and 16.7 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 7.1 °, 11.2 °, and 15.3 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 7.1 °, 11.2 °, and 16.7 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 7.1 °, 15.3 °, and 16.7 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 11.2 °, 15.3 °, and 16.7 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 10.6 °, 15.3 °, and 16.7 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 10.6 °, 11.2 °, and 16.7 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 10.6 °, 11.2 °, and 15.3 ° 2 Θ ± 0.2 ° 2 Θ.
Form VI of Compound 1
The present disclosure provides a crystalline form of compound 1, referred to as form VI of compound 1. In some embodiments, form VI of compound 1 is an anisole solvate. In some embodiments, form VI of compound 1 is characterized by an XRPD pattern comprising at least three peaks selected from 7.2 °, 10.5 °, 11.1 °, 15.2 °, and 16.6 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, form VI of compound 1 is characterized by an XRPD pattern substantially the same as the pattern shown in figure 10.
Form VI of compound 1 can also be characterized using TG or DSC. In some embodiments, form VI of compound 1 is characterized by a TG thermogram substantially the same as the pattern shown in fig. 11 and/or a DSC thermogram substantially the same as the pattern shown in fig. 12.
In some embodiments, form VI of compound 1 is characterized by having at least two of:
a) The XRPD pattern comprises at least three peaks selected from 7.2 °, 10.5 °, 11.1 °, 15.2 °, and 16.6 ° 2 Θ ± 0.2 ° 2 Θ;
b) The TG thermogram was substantially the same as the pattern shown in fig. 11; and
c) The DSC thermogram is substantially the same as the pattern shown in figure 12.
In some embodiments, the XRPD pattern comprises peaks at 7.2 °, 10.5 °, 11.1 °, 15.2 °, and 16.6 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 7.2 °, 10.5 °, and 11.1 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 7.2 °, 10.5 °, and 15.2 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 7.2 °, 10.5 °, and 16.6 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 7.2 °, 11.1 °, and 15.2 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 7.2 °, 11.1 °, and 16.6 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 7.2 °, 15.2 °, and 16.6 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 11.1 °, 15.2 °, and 16.6 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 10.5 °, 11.1 °, and 15.2 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 10.5 °, 11.1 °, and 16.6 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 10.5 °, 15.2 °, and 16.6 ° 2 Θ ± 0.2 ° 2 Θ.
Form VII of Compound 1
The present disclosure provides a crystalline form of compound 1, referred to as form VII of compound 1. In some embodiments, form VII of compound 1 is isopropanol solvate. In some embodiments, form VII of compound 1 is characterized by an XRPD pattern comprising at least three peaks selected from 8.4 °, 10.6 °, 13.6 °, 15.4 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, form VII of compound 1 is characterized by an XRPD pattern substantially the same as the pattern shown in figure 13.
Form VII of compound 1 can also be characterized using TG or DSC. In some embodiments, form VII of compound 1 is characterized by a TG thermogram substantially the same as the pattern shown in figure 14 and/or a DSC thermogram substantially the same as the pattern shown in figure 15.
In some embodiments, form VII of compound 1 is characterized by having at least two of:
a) The XRPD pattern comprises at least three peaks selected from 8.4 °, 10.6 °, 13.6 °, 15.4 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ;
b) The TG thermogram is substantially the same as the pattern shown in fig. 14; and
c) The DSC thermogram is substantially the same as the one set forth in figure 15.
In some embodiments, the XRPD pattern comprises peaks at 8.4 °, 10.6 °, 13.6 °, 15.4 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 8.4 °, 10.6 °, and 13.6 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 8.4 °, 10.6 °, and 15.4 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 8.4 °, 10.6 °, and 18.8 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 8.4 °, 13.6 °, and 15.4 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 8.4 °, 13.6 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 8.4 °, 15.4 °, and 18.8 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 10.6 °, 13.6 °, and 15.4 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 10.6 °, 13.6 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 10.6 °, 15.4 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 13.6 °, 15.4 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ.
Form VIII of Compound 1
The present disclosure provides a crystalline form of compound 1, designated form VIII of compound 1. In some embodiments, form VIII of compound 1 is a dioxane solvate. In some embodiments, form VIII of compound 1 is characterized by an XRPD pattern comprising at least three peaks selected from 7.4 °, 10.6 °, 13.7 °, 15.2 °, and 18.7 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, form VIII of compound 1 is characterized by an XRPD pattern substantially the same as the pattern shown in figure 16.
Form VIII of compound 1 can also be characterized using TG or DSC. In some embodiments, form VIII of compound 1 is characterized by a TG thermogram substantially the same as the pattern shown in fig. 17 and/or a DSC thermogram substantially the same as the pattern shown in fig. 18.
In some embodiments, form VIII of compound 1 is characterized by having at least two of the following:
a) The XRPD pattern comprises at least three peaks selected from 7.4 °, 10.6 °, 13.7 °, 15.2 °, and 18.7 ° 2 Θ ± 0.2 ° 2 Θ;
b) The TG thermogram was substantially the same as the pattern shown in fig. 17; and
c) The DSC thermogram is substantially the same as the one set forth in figure 18.
In some embodiments, the XRPD pattern comprises peaks at 7.4 °, 10.6 °, 13.7 °, 15.2 °, and 18.7 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 7.4 °, 10.6 °, and 13.7 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 7.4 °, 10.6 °, and 15.2 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 7.4 °, 10.6 °, and 18.7 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 7.4 °, 13.7 °, and 15.2 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 7.4 °, 13.7 °, and 18.7 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 7.4 °, 15.2 °, and 18.7 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 10.6 °, 13.7 °, and 15.2 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 10.6 °, 13.7 °, and 18.7 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 10.6 °, 15.2 °, and 18.7 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 13.7 °, 15.2 °, and 18.7 ° 2 Θ ± 0.2 ° 2 Θ.
Form IX of Compound 1
The present disclosure provides a crystalline form of compound 1, designated form IX of compound 1. In some embodiments, form IX of compound 1 is an α, α, α -trifluorotoluene solvate. In some embodiments, form IX of compound 1 is characterized by an XRPD pattern substantially the same as the pattern shown in figure 19.
Form IX of compound 1 can also be characterized using TG or DSC. In some embodiments, form IX of compound 1 is characterized by a TG thermogram substantially the same as the pattern shown in fig. 20. In some embodiments, form IX of compound 1 is characterized by a DSC thermogram substantially the same as the pattern shown in figure 21.
In some embodiments, form IX of compound 1 is characterized as having at least two of the following:
a) The XRPD pattern is substantially the same as the pattern shown in figure 19;
b) The TG thermogram was substantially the same as the pattern shown in fig. 20; and
c) The DSC thermogram is substantially the same as the pattern shown in figure 21.
Form X of Compound 1
The present disclosure provides a crystalline form of compound 1, referred to as form X of compound 1. In some embodiments, form X of compound 1 is trifluoroethanol solvate. In some embodiments, form X of compound 1 is characterized by an XRPD pattern comprising at least three peaks selected from 4.6 °, 9.1 °, 9.6 °, 17.4 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, form X of compound 1 is characterized by an XRPD pattern substantially the same as the pattern shown in figure 22.
Form X of compound 1 can also be characterized using TG or DSC. In some embodiments, form X of compound 1 is characterized by a TG thermogram substantially the same as the pattern shown in figure 23 and/or a DSC thermogram substantially the same as the pattern shown in figure 24.
In some embodiments, form X of compound 1 is characterized by having at least two of the following:
a) The XRPD pattern comprises at least three peaks selected from 4.6 °, 9.1 °, 9.6 °, 17.4 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ;
b) The TG thermogram was substantially the same as the pattern shown in fig. 23; and
c) The DSC thermogram is substantially the same as the one shown in figure 24.
In some embodiments, the XRPD pattern comprises peaks at 4.6 °, 9.1 °, 9.6 °, 17.4 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 4.6 °, 9.1 °, and 9.6 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 4.6 °, 9.1 °, and 17.4 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 4.6 °, 9.1 °, and 18.8 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 4.6 °, 9.6 °, and 17.4 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 4.6 °, 9.6 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 4.6 °, 17.4 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 9.1 °, 9.6 °, and 17.4 ° 2 θ ± 0.2 ° 2 θ. In some embodiments, the XRPD pattern comprises peaks at 9.1 °, 9.6 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 9.1 °, 17.4 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ. In some embodiments, the XRPD pattern comprises peaks at 9.6 °, 17.4 °, and 18.8 ° 2 θ ± 0.2 ° 2 θ.
Form XI of Compound 1
The present disclosure provides a crystalline form of compound 1, referred to as form XI of compound 1. In some embodiments, form XI of compound 1 is a DMF solvate. In some embodiments, form XI of compound 1 is characterized by an XRPD pattern substantially the same as the pattern shown in figure 30.
Form XI of compound 1 can also be characterized using TG or DSC. In some embodiments, form XI of compound 1 is characterized by a TG thermogram substantially the same as the pattern shown in figure 31 (top panel). In some embodiments, form XI of compound 1 is characterized by a DSC thermogram substantially the same as the pattern shown in figure 31 (lower panel).
In some embodiments, form XI of compound 1 is characterized as having at least two of:
a) The XRPD pattern is substantially the same as the pattern shown in figure 30;
b) The TG thermogram was substantially the same as the pattern shown in fig. 31 (upper panel); and
c) The DSC thermogram is substantially the same as the pattern shown in figure 31 (lower panel).
Form XII of Compound 1
The present disclosure provides a crystalline form of compound 1, referred to as form XII of compound 1. In some embodiments, form XII of compound 1 is characterized by an XRPD pattern substantially the same as the pattern shown in figure 32.
Form XII of compound 1 can also be characterized using TG or DSC. In some embodiments, form XII of compound 1 is characterized by a TG thermogram substantially the same as the pattern shown in fig. 33 (top panel). In some embodiments, form XII of compound 1 is characterized by a DSC thermogram substantially the same as the pattern shown in figure 33 (lower panel).
In some embodiments, form XII of compound 1 is characterized as having at least two of the following:
an xrpd pattern substantially the same as the pattern shown in figure 32;
tg thermogram substantially the same as the pattern shown in fig. 33 (upper panel); and
a dsc thermogram substantially the same as the pattern shown in figure 33 (lower panel).
In some embodiments, the crystalline form of compound I disclosed herein may be characterized by an XRPD pattern having the peaks listed in table 2. All peaks are tabulated at an angle 2 theta + -0.2 deg. 2 theta.
Solubility of crystalline forms I and II of Compound 1
The water solubility of form II is summarized in table 3:
* GCDC is glycochenodeoxycholic acid sodium salt.
Form II of compound 1 was found to be more soluble than form I of compound 1, and its water solubility is summarized in table 4:
form II of compound 1 shows higher water solubility at pH 6.8 (which is in the pH range of the small intestine) than form 1 of compound 1. While not being bound by any particular theory, the higher solubility of form II of compound 1 at this physiologically relevant pH may result in one or more pharmacokinetic or pharmacodynamic advantages, such as higher bioavailability, lower dose to achieve therapeutic plasma concentrations, and lower interpatient variability in efficacy at a particular dose. Higher water solubility may also create advantages in formulation development by avoiding or reducing the need for methods commonly used to enhance solubility or dissolution, including particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactants, and complexation.
Preparation of the crystalline forms of the present disclosure
Form II to form XII of compound 1 can be used during the synthesis or production of form I of compound 1. Form I of compound 1 and methods of making form I of compound 1 are described in U.S. patent No. 9,758,528, which is incorporated herein by reference in its entirety, particularly with respect to synthesis and crystallization methods. The XRPD pattern of form I of compound 1 is depicted in figure 25. Methods for preparing compound 1 prior to crystallization are described in us patent 7,300,935, us patent No. 8,058,280, us patent No. 8,735,401, and us patent No. 9,346,822, which are incorporated herein by reference in their entirety.
In some embodiments, form I of compound 1 can be prepared by using any one of form II of compound 1, form III of compound 1, form IV of compound 1, form V of compound 1, form VI of compound 1, form VII of compound 1, form VIII of compound 1, form IX of compound 1, form X of compound 1, form XI of compound 1, form XII of compound 1, or any combination thereof. In some embodiments, form I of compound 1 can be prepared using any solvated form of compound 1, e.g., form V of compound 1, form VI of compound 1, form VII of compound 1, form VIII of compound 1, form IX of compound 1, form X of compound 1, form XI of compound 1, form XII of compound 1, or any combination thereof. For example, form I of Compound 1 can be prepared by dissolving form V of Compound 1 in DMSO at a temperature of about 35 ℃ +/-5 ℃. Ethanol was then added to the mixture. The mixture was then filtered while maintaining the temperature of the mixture at about 35 ℃ +/-5 ℃ and the solids were washed with ethanol, and the mixture was stirred at about 35 ℃ +/-5 ℃ for about one hour, cooled to about 25 ℃ +/-5 ℃ and stirred for about 12 hours or more. The resulting precipitate provided form I of compound 1.
In some embodiments, form III of compound I is converted to form IV by heating above about 52 ℃. In certain such embodiments, form I recrystallizes upon melting of form IV, which occurs between about 197 ℃ and about 201 ℃. In certain such embodiments, form IV cannot be isolated due to a reversible change to form III at room temperature under normal humidity. The conversion of forms II, III and IV to form I is illustrated in figure 27.
The present disclosure provides a process for preparing an amorphous form of compound 1. In certain such embodiments, form I of compound 1 is dissolved in dimethyl sulfoxide and 1,4-dioxane at a ratio (v/v) of about 1. Dimethyl sulfoxide and 1,4-dioxane were then evaporated by vacuum freeze drying to provide the amorphous form of compound 1.
The present disclosure provides a process for preparing form II of compound 1. In certain such embodiments, form 1 of compound 1 is dissolved in a mixture of DMF and acetone (about 6,94,v/v) at about 25 ℃. The resulting solution was stirred at a temperature of about-15 ℃ to about-25 ℃ for about 3 days to produce a suspension. The solid formed was isolated by vacuum filtration and dried under vacuum at about 60 ℃ for about 4 hours to provide form II of compound 1.
In some embodiments, the method for preparing form II of compound 1 comprises dissolving form 1 of compound 1 in a mixture of DMF and acetone (about 80,v/v) at about 40 ℃. Acetone at room temperature was then added to the mixture to achieve a DMF to acetone ratio of about 12.5 v/v. The mixture is then seeded with about 0.5% by weight of form II crystals. The mixture was placed in a freezer overnight at about-15 ℃ to about-25 ℃, after which the resulting suspension was vacuum filtered, the wet cake was washed with cold acetone, and vacuum dried at about 62 ℃ to about 65 ℃ for about 5 hours to provide form II of compound 1.
In some embodiments, the method for preparing form II of compound 1 comprises dissolving form 1 of compound 1 in DMF at about 40 ℃. Acetone at room temperature was added to the mixture to achieve a DMF to acetone ratio of about 10 90v/v. The mixture was then inoculated with about 0.5% by weight of form II. The mixture was placed in a freezer overnight at about-15 ℃ to about-25 ℃, after which the resulting suspension was vacuum filtered, the wet cake was washed with cold acetone, and vacuum dried at about 62 ℃ to about 65 ℃ for about 5 hours to provide form II of compound 1.
The present disclosure provides a process for preparing form III of compound 1. In some embodiments, form III of compound 1 is prepared by dissolving form 1 of compound 1 in DMF, precipitating with water, and storing at about-10 ℃ for about three days.
The present disclosure provides a process for preparing form IV of compound 1. In certain such embodiments, form III of compound I is converted to anhydrate form IV by heating form III to between about 79 ℃ to about 197 ℃.
The present disclosure provides a process for preparing form V of compound 1. In certain such embodiments, the amorphous form of compound 1 is dissolved in toluene at about 55 ℃ to produce a solution of about 10 mg/mL. Toluene was then evaporated at about 55 ℃ by a stream of nitrogen to afford form V of compound 1.
The present disclosure provides a process for preparing form VI of compound 1. In certain such embodiments, the amorphous form of compound 1 is dissolved into anisole at about 55 ℃ to produce a solution of about 10 mg/mL. Approximately equal volumes of heptane were added to the anisole solution at about 55 deg.C to produce a solution of about 5 mg/mL. Anisole and heptane were then evaporated at about 55 ℃ by a stream of nitrogen to provide form VI of compound 1.
The present disclosure provides a process for preparing form VII of compound 1. In certain such embodiments, the amorphous form of compound 1 is dissolved into 2-propanol at about 55 ℃ to produce a solution of about 10 mg/mL. About 2.5 volumes of water were added to the 2-propanol solution at about 55 ℃ to make a solution of about 2.9 mg/mL. The solution was cooled from about 55 c to about 10 c with stirring at a rate of about 3 c/hour. The crystalline solid was collected by filtration to provide form VII of compound 1.
The present disclosure provides a process for preparing form VIII of compound 1. In certain such embodiments, form I of compound 1 is dispersed into a mixture of 1,4-dioxane and water (about 1, v/v) to make a slurry state at a concentration of about 20 mg/mL. The slurry was aged by stirring at about 25 ℃ for about three days. The dispersed powder was collected by filtration to provide form VIII of compound 1.
The present disclosure provides a process for preparing form IX of compound 1. In certain such embodiments, the amorphous form of compound 1 is dissolved into α, α, α -trifluorotoluene at about 55 ℃ to produce a solution of about 10 mg/mL. About equal volumes of heptane were added to the α, α, α -trifluorotoluene solution at about 55 ℃ to make a solution of about 5 mg/mL. The α, α, α -trifluorotoluene and heptane were then evaporated by a nitrogen stream at about 55 ℃ to provide form IX of compound 1.
The present disclosure provides a process for preparing form X of compound 1. In certain such embodiments, the amorphous form of compound 1 is dissolved into trifluoroethanol at about 55 ℃ to produce a solution of about 200 mg/mL. To the trifluoroethanol solution was added about equal volume of diisopropyl ether at about 55 ℃ to make a solution of about 100 mg/mL. The solution was cooled from about 55 ℃ to about 10 ℃ at a rate of about 3 ℃ per hour with stirring. The crystalline solid in suspension was collected by filtration to provide form X of compound 1.
The present disclosure provides several methods for preparing form XI of compound 1. In certain such embodiments, form I of compound 1 is dissolved in DMF at ambient temperature. The resulting clear solution was cooled to about-10 ℃. An aliquot of methyl tert-butyl ether (MTBE) was added to achieve a DMF to MTBE volume ratio of about 50 and the seeds of form II of compound 1 were added. An additional amount of MTBE was added to achieve a DMF to MTBE volume ratio of about 25. The resulting solution was stirred at about-10 ℃ overnight to provide a suspension. After stirring at about-10 ℃ for a total of about 4 days, the solid was isolated by vacuum filtration cold and washed with cold MTBE to provide form XI of compound 1.
In some embodiments, the method for preparing form XI of compound 1 comprises dissolving form I of compound 1 in DMF at ambient temperature. The resulting solution was cooled to about-10 ℃. An aliquot of isopropanol was added to achieve a DMF to isopropanol volume ratio of about 50 and seeds of form II of compound 1 were added. The solution was allowed to stir at about-10 ℃ overnight. After stirring at about-10 ℃ for a total of about 4 days, the solids of the resulting suspension were diluted with cold isopropanol and isolated by vacuum filtration to provide compound 1, form XI.
The present disclosure provides a process for preparing form XII of compound 1. In certain such embodiments, form I of compound 1 is dissolved in DMF at ambient temperature. The resulting solution was added dropwise to acetone with stirring without causing precipitation. The DMF to acetone volume ratio was about 6. The solution was allowed to stir at about-15 ℃ to about-25 ℃ for about 2 days, and the resulting solution was stirred for an additional about 1 day to produce a suspension. The solid was isolated by cold separation by vacuum filtration to afford form XII of compound 1.
In some embodiments, the process for preparing form XII of compound 1 comprises dissolving form I of compound 1 in DMF acetone (about 80 (v/v)). Additional aliquots of DMF were added until complete dissolution was observed, reaching a DMF to acetone ratio of about 85 (v/v). The resulting solution was stirred at ambient temperature and acetone was added slowly to achieve a DMF to acetone ratio of about 12.5. The resulting solution was seeded with form II of compound 1 and the resulting solution was cooled to about-15 ℃ to about-25 ℃ overnight. The solid was isolated by cold filtration at about-15 ℃ to about-25 ℃ under vacuum. The solid was washed with cold acetone at about-15 ℃ to about-25 ℃ to provide form XII of compound 1.
In some embodiments, the process for preparing form XII of compound 1 comprises dissolving form I of compound 1 in DMF at about 40 ℃. Additional aliquots of DMF were added until complete dissolution was observed. The resulting solution was stirred at ambient temperature and acetone was added slowly to achieve a DMF to acetone ratio of about 11. The clear solution was inoculated with form II of compound 1. Additional acetone was added to achieve a DMF to acetone ratio of about 10 (v/v) and the sample was allowed to stir at ambient temperature, resulting in a suspension that was maintained at about-15 ℃ to about-25 ℃ overnight. The solid was isolated by cold filtration under vacuum and washed with cold acetone to afford form XII of compound 1.
Pharmaceutical composition
The disclosed crystalline forms may be used alone, but if administered to a subject, will generally be administered in the form of a pharmaceutical composition in which one or more of the disclosed crystalline forms of compound 1 are combined with a pharmaceutically acceptable carrier. Conventional procedures for selecting and preparing suitable pharmaceutical compositions are described, for example, in "Pharmaceuticals-The Science of Dosage Form Designs," m.e. aulton, churchlill Livingstone,1988, which is incorporated herein by reference in its entirety.
As used in this disclosure, the term "carrier" may encompass carriers, excipients, and diluents and may refer to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying an agent (such as a crystalline form of the present disclosure) or transporting an agent (such as a crystalline form of the present disclosure) from one organ or portion of a subject's body to another organ or portion of the body. The carrier should be selected based on compatibility and the release profile properties of the desired dosage form. Exemplary carrier materials can include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, spray-dried dispersions, and the like. See, e.g., oover, john e., remington's Pharmaceutical Sciences, mack Publishing co., easton, pa.1975.
In some embodiments, the present disclosure provides a pharmaceutical composition comprising one or more of the crystalline forms disclosed herein. In some embodiments, the present disclosure provides a pharmaceutical composition comprising only one crystalline form disclosed herein. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form II of compound 1. In other embodiments, the present disclosure provides a pharmaceutical composition comprising two or more of the crystalline forms disclosed herein. For example, a pharmaceutical composition comprising compound 1 can comprise form I of compound 1 and form II of compound 1.
In some embodiments, the present disclosure provides a pharmaceutical composition comprising form III of compound 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form V of compound 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form VI of compound 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form VII of compound 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form VIII of compound 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form IX of compound 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form X of compound 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form XI of compound 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form XII of compound 1.
In some embodiments, the present disclosure provides a pharmaceutical composition comprising form II of compound 1 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form I and form II of compound 1 and a pharmaceutically acceptable carrier.
In some embodiments, the present disclosure provides a pharmaceutical composition comprising form III of compound 1 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form V of compound 1 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form VI of compound 1 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form VII of compound 1 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form VIII of compound 1 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form IX of compound 1 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form X of compound 1 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form XI of compound 1 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising form XII of compound 1 and a pharmaceutically acceptable carrier.
In some embodiments, the present disclosure provides a pharmaceutical composition comprising two or more of form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising two or more of form I, form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 and a pharmaceutically acceptable carrier.
Depending on the mode of administration, the pharmaceutical composition will comprise about 0.05 to about 99 weight percent (percent by weight), more specifically about 0.05 to about 80 weight percent, still more specifically about 0.10 to about 70 weight percent, even more specifically about 0.10 to about 50 weight percent of one or more of the disclosed crystalline forms, all weight percentages being based on the total composition.
The pharmaceutical compositions of the present disclosure may comprise a therapeutically effective amount of one or more of the disclosed crystalline forms formulated with one or more pharmaceutically acceptable carriers. Examples of the pharmaceutically acceptable carrier include sugars such as lactose, dextrose, mannitol, glucose, and sucrose; starches such as starch derived from corn, wheat or potato and other pharmaceutical grade starches such as sodium starch glycolate; cellulose and its derivatives such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, cellulose acetate and microcrystalline cellulose; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; a phosphate buffer solution; lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; a coating agent; sweetening, flavoring and perfuming agents; preservatives and antioxidants.
Methods of treatment and uses
The present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more crystalline forms described herein, or a pharmaceutical composition comprising one or more crystalline forms described herein, thereby treating the disorder in a subject in need thereof.
In some embodiments of the methods and uses of the present disclosure, the disorder is a hormone-dependent condition. The hormone-dependent conditions may include sex hormone-dependent cancers (e.g., prostate cancer, uterine cancer, breast cancer, and ovarian cancer), bone metastases of sex hormone-dependent cancers, prostatic hypertrophy, uterine fibroids (leiomyoma) adenomas, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multifocal ovarian syndrome, polycystic ovarian syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, menstrual bleeding, and symptoms associated with these conditions. Such symptoms may include anemia, irregular menstrual cycles, drip bleeding, inflammation, pain, fatigue, urinary tract obstruction, frequent urination, incontinence, constipation, anxiety, sleep disorders, decreased quality of life, difficulty with daily activity, female sexual dysfunction, and depression. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer. Other conditions for which compound 1 may be useful in treatment are described in us patent 7,300,935, us patent no 8,058,280, us patent no 8,735,401, us patent no 9,346,822, WO2018060501, and WO2018060463, which are incorporated herein by reference in their entirety.
In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is prostate cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is uterine cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is breast cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is ovarian cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is uterine leiomyoma. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is menstrual bleedings associated with uterine leiomyoma. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is endometriosis. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is pain associated with endometriosis. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is adenomyosis. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is menstrual bleedings.
A "patient" or "subject" is a mammal. Examples of mammals can include, but are not limited to, any member of the class mammalia, including humans; non-human primates such as chimpanzees, monkeys, baboons, and rhesus monkeys; cattle, horses, sheep, goats, and pigs; rabbits, dogs, and cats; and rodents such as rats, mice and guinea pigs. In some embodiments, the patient or subject is a human.
The term "effective amount" or "therapeutically effective amount" when used in conjunction with one or more crystalline forms or pharmaceutical compositions of the present disclosure may refer to an amount of the one or more crystalline forms or pharmaceutical compositions sufficient to provide a desired biological result. The result may be a reduction and/or alleviation of the signs, symptoms, or causes of a disorder, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use can be the amount of a pharmaceutical composition comprising one or more crystalline forms as disclosed herein that is required to provide a clinically significant reduction in the disorder. An appropriate "effective amount" in any individual case can be determined by one of ordinary skill in the art using routine experimentation.
As used herein, the term "treatment" or its cognate is intended to indicate a delay in the development of the disorder; and/or reduce the severity of such symptoms that are about to occur or are expected to occur. Thus, these terms may include ameliorating existing symptoms of the disorder; prevention of other symptoms; ameliorating or preventing the root cause of the symptoms; inhibiting a disorder, e.g., arresting its development; relieving the symptoms; causing regression of the condition; alleviating symptoms caused by the disorder; or to stop or alleviate symptoms of the disorder.
As used in this disclosure, the term "administering" may refer to administering one or more crystalline forms or pharmaceutical compositions of the present disclosure directly to a subject.
The present disclosure provides a method of treating a disorder comprising administering an effective amount of form II of compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder comprising administering an effective amount of form III of compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder comprising administering an effective amount of form V of compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder comprising administering an effective amount of form VI of compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder comprising administering an effective amount of form VII of compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder comprising administering an effective amount of form VIII of compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder comprising administering an effective amount of form IX of compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder comprising administering an effective amount of form X of compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder comprising administering an effective amount of form XI of compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder comprising administering an effective amount of form XII of compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder comprising administering an effective amount of a mixture of two or more of form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder comprising administering an effective amount of a mixture of two or more of form I, form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition.
The present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions of the present disclosure, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising form II of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising form III of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising form V of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising form VI of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising form VII of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising form VIII of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising form IX of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising form X of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising form XI of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising form XII of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising a mixture of two or more of form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising a mixture of two or more of form I, form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition.
The present disclosure provides one or more crystalline forms of the present disclosure or one or more pharmaceutical compositions of the present disclosure for use in treating a disorder in a subject in need thereof. In some embodiments, the one or more crystalline forms comprise form II of compound 1. In some embodiments, the one or more crystalline forms comprise form III of compound 1. In some embodiments, the one or more crystalline forms comprise form V of compound 1. In some embodiments, the one or more crystalline forms comprise form VI of compound 1. In some embodiments, the one or more crystalline forms comprise form VII of compound 1. In some embodiments, the one or more crystalline forms comprise form VIII of compound 1. In some embodiments, the one or more crystalline forms comprise form IX of compound 1. In some embodiments, the one or more crystalline forms comprise form X of compound 1. In some embodiments, the one or more crystalline forms comprise form XI of compound 1. In some embodiments, the one or more crystalline forms comprise form XII of compound 1. In some embodiments, the one or more crystalline forms is a mixture of two or more of form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1. In some embodiments, the one or more crystalline forms is a mixture of two or more of form I, form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise one or more of the crystalline forms disclosed herein. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise form II of compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise form III of compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise form V of compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise form VI of compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise form VII of compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise form VIII of compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise form IX of compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise form X of compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise form XI of compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise form XII of compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise a mixture of two or more of form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise a mixture of two or more of form I, form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1. In some embodiments, the disorder is a hormone-dependent condition.
The present disclosure provides one or more crystalline forms of the present disclosure for use in treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of form II of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of form III of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of form V of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of form VI of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of form VII of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of form VIII of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of form IX of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of form X of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of form XI of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of form XII of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of a mixture of two or more of form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition. In some embodiments, the present disclosure provides the use of a mixture of two or more of form I, form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition.
The present disclosure provides one or more pharmaceutical compositions of the present disclosure for use in treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein for use in treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form II of compound 1 for use in treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form III of compound 1 for use in treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form V of compound 1 for use in treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form VI of compound 1 for use in treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form VII of compound 1 for use in treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form VIII of compound 1 for use in treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form IX of compound 1 for use in treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form X of compound 1 for use in treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form XI of compound 1 for use in treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising form XII of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising a mixture of two or more of form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising a mixture of two or more of form I, form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition.
The present disclosure provides for the use of one or more crystalline forms of the present disclosure in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of form II of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of form III of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of form V of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides use of form VI of compound 1 in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides for the use of form VII of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of form VIII of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of form IX of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of form X of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides use of form XI of compound 1 in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides for the use of form XII of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of a mixture of two or more of form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of a mixture of two or more of form I, form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the disorder is a hormone-dependent condition.
The present disclosure provides for the use of one or more pharmaceutical compositions of the present disclosure in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein for use in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising form II of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising form III of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising form V of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising form VI of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising form VII of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising form VIII of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising form IX of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising form X of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising form XI of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising form XII of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising a mixture of two or more of form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising a mixture of two or more of form I, form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 in the manufacture of a medicament for the treatment of a disorder. In some embodiments, the disorder is a hormone-dependent condition.
The present disclosure provides one or more crystalline forms of the present disclosure for use as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of form II of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of form III of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of form V of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of form VI of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of form VII of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of form VIII of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of form IX of compound 1 as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of form X of compound 1 as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of form XI of compound 1 as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of form XII of compound 1 as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of a mixture of two or more of form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of a mixture of two or more of form I, form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the disorder is a hormone-dependent condition.
The present disclosure provides one or more pharmaceutical compositions of the present disclosure for use as a medicament for treating a disorder. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising one or more of the crystalline forms disclosed herein for use as a medicament for treating a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising form II of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising form III of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising form V of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form VI of compound 1 for use as a medicament for treating a disorder. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form VII of compound 1 for use as a medicament for treating a disorder. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form VIII of compound 1 for use as a medicament for treating a disorder. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form IX of compound 1 for use as a medicament for treating a disorder. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form X of compound 1 for use as a medicament for treating a disorder. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising form XI of compound 1 for use as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising form XII of compound 1 as a medicament for treating a disorder. In some embodiments, the present disclosure provides for the use of one or more pharmaceutical compositions comprising a mixture of two or more of form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising a mixture of two or more of form I, form II, form III, form V, form VI, form VII, form VIII, form IX, form X, form XI, or form XII of compound 1 as a medicament for the treatment of a disorder. In some embodiments, the disorder is a hormone-dependent condition.
In some embodiments of the methods and uses of the present disclosure, only one pharmaceutical composition of the present disclosure is used in the method or use. In some embodiments of the methods and uses of the present disclosure, only one crystalline form of the present disclosure is used in the methods or uses.
For the therapeutic uses mentioned herein, the dosage administered will, of course, vary with the crystalline form or forms or pharmaceutical compositions employed, the mode of administration, the treatment desired and the condition indicated. For example, if inhaled, the daily dose of one or more crystalline forms of the present disclosure can range from about 0.05 micrograms per kilogram body weight (μ g/kg) to about 100 micrograms per kilogram body weight (μ g/kg). Alternatively, if the one or more crystalline forms or pharmaceutical compositions are administered orally, the daily dose of the one or more crystalline forms of the present disclosure can range from about 0.01 micrograms per kilogram of body weight (μ g/kg) to about 100 milligrams per kilogram of body weight (mg/kg).
However, it is to be understood that the total daily amount of one or more crystalline forms or pharmaceutical compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the condition being treated and the severity of the condition; the activity of the particular crystalline form employed; the specific pharmaceutical composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular crystalline form employed; the duration of the treatment; a drug in combination or concomitant with the specific crystalline form employed; and similar factors well known in the medical arts. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of one or more of the crystalline forms or pharmaceutical compositions disclosed herein required to treat, counter, or arrest the progress of the condition.
Combination therapy
In some embodiments, one or more of the crystalline forms or pharmaceutical compositions described herein can be used alone or together or administered in combination, or in combination with one or more other therapeutic agents or pharmaceutical compositions. Co-administration or combined use may refer to administration of two or more different compounds, crystalline forms, or any form of pharmaceutical composition such that a second compound, crystalline form, or pharmaceutical composition is administered while a previously administered compound, crystalline form, or pharmaceutical composition is still effective in vivo. For example, the different compounds, crystalline forms or pharmaceutical compositions may be administered in the same formulation or in separate formulations or simultaneously or sequentially, or by separate administration of a single therapeutic component. In some embodiments, the different compounds, crystalline forms, or pharmaceutical compositions may be administered within about one hour, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, or about one week apart from each other. Thus, individuals receiving such treatment may benefit from the combined effects of different compounds, crystalline forms, or pharmaceutical compositions.
In some embodiments, one or more crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with one or more other crystalline forms or pharmaceutical compositions of the present disclosure in methods or uses of the present disclosure. In certain such embodiments, the combination with one or more other crystalline forms or pharmaceutical compositions of the present disclosure is used in a method of treating one or more of the conditions listed herein.
In some embodiments, one or more of the crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with estradiol or a corresponding amount of estradiol equivalent. In some embodiments, one or more of the crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with progesterone. In some embodiments, one or more of the crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with estradiol or a corresponding amount of estradiol equivalent and progesterone. In some embodiments, the progestin is norethindrone acetate.
In some embodiments, combinations of one or more of the crystalline forms or pharmaceutical compositions provided herein or other known agents or pharmaceutical compositions with one or more of the crystalline forms or pharmaceutical compositions provided herein are formulated into pharmaceutical compositions and medicaments useful in the methods and uses of the present disclosure. The present disclosure also provides the use of such a combination in the treatment of one or more of the conditions listed herein.
In some embodiments of the present disclosure, one or more crystalline forms or pharmaceutical compositions of the present disclosure are administered at a subtherapeutic dose, wherein a subtherapeutic dose is a dose that would be insufficient to treat one of the conditions listed herein if administered alone.
Reagent kit
In some embodiments, the present disclosure also provides a pharmaceutical package or kit comprising one or more containers filled with at least one crystalline form or pharmaceutical composition of the present disclosure. Optionally, such containers may be accompanied by a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects (a) approval by the agency of its manufacture, use or sale for human administration, (b) instructions for use, or both.
The foregoing applies to any of the crystalline forms, pharmaceutical compositions, methods and uses described herein. In particular, the present disclosure encompasses any combination of the features of such crystalline forms, pharmaceutical compositions, methods and uses (alone or in combination) with the features described for the various kits described in this section.
Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are described herein. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are herein incorporated by reference in their entirety.
Each embodiment described herein can be used alone or in combination with any one or more other embodiments.
Detailed description of the embodiments
Some embodiments of the present disclosure include those of embodiment I:
one crystalline form of embodiment I-1.N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, which is designated as form II of compound 1.
Embodiment I-2 the crystalline form of embodiment I-1 characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ.
Embodiment I-3 the crystalline form of embodiment I-1, characterized by an X-ray powder diffraction pattern comprising at least five peaks selected from 7.2 °, 9.7 °, 10.7 °, 13.1 °, 15.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ.
Embodiment I-4 the crystalline form of embodiment I-1, characterized by an X-ray powder diffraction pattern comprising peaks at 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 θ ± 0.2 ° 2 θ.
Embodiment I-5 the crystalline form of embodiment I-4 wherein the X-ray powder diffraction pattern comprises one or more peaks selected from 7.2 °, 13.1 °, and 15.7 ° ± 0.2 ° 2 Θ.
Embodiment I-6 the crystalline form of any one of embodiments I-1 to I-5, characterized by an XRPD pattern substantially the same as the pattern shown in figure 1.
Embodiment I-7 the crystalline form of any one of embodiments I-1 to I-6, characterized by beginning degradation between about 174 ℃ to about 176 ℃.
Embodiment I-8 the crystalline form of any one of embodiments I-1 to I-7, characterized by beginning degradation at about 175 ℃.
Embodiment I-9 the crystalline form of any one of embodiments I-1 to I-8, characterized by a thermogravimetric analysis (TG) thermogram substantially the same as the pattern shown in figure 2.
Embodiment I-10 the crystalline form of any one of embodiments I-1 to I-9, characterized by an onset of melting between about 179 ℃ to about 181 ℃.
Embodiment I-11 the crystalline form of any one of embodiments I-1 to I-10 characterized by an onset of melting at about 180 ℃.
Embodiment I-12 the crystalline form of any one of embodiments I-1 to I-11, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an exothermic peak at between about 191 ℃ and about 194 ℃.
Embodiment I-13 the crystalline form of any one of embodiments I-1 to I-12 characterized by a DSC thermogram comprising an exothermic peak at about 192 ℃.
Embodiment I-14 the crystalline form of any one of embodiments I-1 to I-13, characterized by a DSC thermogram substantially the same as the one set forth in figure 3.
Embodiment I-15. The crystalline form of embodiment I-1, characterized by having at least two of the following:
a) The XRPD pattern comprises at least three peaks selected from 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ;
b) Degradation started at about 175 ℃ as measured by TG; and
c) As measured by DSC, has an exothermic peak at about 192 ℃.
Embodiment I-16.N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea a crystalline form referred to as form III of Compound 1.
Embodiment I-17 the crystalline form of embodiment I-16 characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.5 °, 9.5 °, 16.8 °, and 18.1 ° 2 θ ± 0.2 ° 2 θ.
Embodiment I-18 the crystalline form of embodiment I-16 characterized by an X-ray powder diffraction pattern comprising at least five peaks selected from 7.5 °, 9.5 °, 12.2 °, 16.6 °, 16.8 °, and 18.1 ° 2 Θ ± 0.2 ° 2 Θ.
Embodiment I-19. The crystalline form of embodiment I-16 characterized by an X-ray powder diffraction pattern comprising peaks at 7.5 °, 9.5 °, 16.8 °, and 18.1 ° 2 θ ± 0.2 ° 2 θ.
Embodiment I-20 the crystalline form of embodiment I-19 wherein the X-ray powder diffraction pattern comprises one or more peaks selected from 12.2 ° and 16.6 ° ± 0.2 ° 2 Θ.
Embodiment I-21 the crystalline form of any one of embodiments I-16 to I-20, characterized by an XRPD pattern substantially the same as the pattern shown in figure 4.
Embodiment I-22 the crystalline form of any one of embodiments I-16 to I-21, characterized in that dehydration is initiated at about 43 ℃ and continued to about 78 ℃.
Embodiment I-23 the crystalline form of any one of embodiments I-16 to I-22, characterized by beginning degradation at about 183 ℃.
Embodiment I-24 the crystalline form of any one of embodiments I-16 to I-23, characterized by a TG thermogram substantially the same as the one set forth in fig. 5.
Embodiment I-25 the crystalline form of any one of embodiments I-16 to I-24, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endothermic peak at about 79 ℃.
Embodiment I-26 the crystalline form of any one of embodiments I-16 to I-25 characterized by a DSC thermogram comprising an exothermic peak at about 205 ℃.
Embodiment I-27 the crystalline form of any one of embodiments I-16 to I-26, characterized by a DSC thermogram substantially the same as the one set forth in figure 6.
Embodiment I-28 the crystalline form of embodiment I-16, characterized by having at least two of the following:
an xrpd pattern comprising at least three peaks selected from 7.5 °, 9.5 °, 16.8 ° and 18.1 ° 2 Θ ± 0.2 ° 2 Θ;
b. dehydration started at about 43 ℃ as measured by TG; and
c. has an endothermic peak at about 79 ℃ as measured by DSC.
Embodiment I-29.A crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, which is designated form V of Compound 1.
Embodiment I-30 the crystalline form of embodiment I-29 characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 7.1 °, 10.6 °, 11.2 °, 15.3 °, and 16.7 ° 2 Θ ± 0.2 ° 2 Θ.
Embodiment I-31. The crystalline form of embodiment I-29 or I-30, characterized by an XRPD pattern substantially the same as the pattern shown in figure 7.
Embodiment I-32 the crystalline form of any one of embodiments I-29 to I-31, characterized by a TG thermogram substantially the same as the one set forth in fig. 8.
Embodiment I-33 the crystalline form of any one of embodiments I-29 to I-32, characterized by a DSC thermogram substantially the same as the one set forth in figure 9.
Embodiments I-34 the crystalline form of embodiments I-29, characterized by having at least two of the following:
an xrpd pattern comprising at least three peaks selected from 7.1 °, 10.6 °, 11.2 °, 15.3 ° and 16.7 ° 2 Θ ± 0.2 ° 2 Θ;
tg thermogram substantially the same as the pattern shown in fig. 8; and
a dsc thermogram substantially the same as the one set forth in figure 9.
Embodiment I-35.N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea in a crystalline form referred to as form VI of Compound 1.
Embodiment I-36 the crystalline form of embodiment I-35 characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 7.2 °, 10.5 °, 11.1 °, 15.2 °, and 16.6 ° 2 Θ ± 0.2 ° 2 Θ.
Embodiment I-37. The crystalline form of embodiment I-35 or I-36, characterized by an XRPD pattern substantially the same as the pattern shown in figure 10.
Embodiment I-38 the crystalline form of any one of embodiments I-35 to I-37, characterized by a TG thermogram substantially the same as the one set forth in fig. 11.
Embodiment I-39 the crystalline form of any one of embodiments I-35 to I-38, characterized by a DSC thermogram substantially the same as the one set forth in figure 12.
Embodiments I-40 the crystalline form of embodiments I-35, characterized by having at least two of the following:
an xrpd pattern comprising at least three peaks selected from 7.2 °, 10.5 °, 11.1 °, 15.2 ° and 16.6 ° 2 Θ ± 0.2 ° 2 Θ;
tg thermogram substantially the same as the pattern shown in fig. 11; and
a dsc thermogram substantially the same as the one set forth in figure 12.
Embodiment I-41.A crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, which is designated form VII of Compound 1.
Embodiment I-42 the crystalline form of embodiment I-41 characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 8.4 °, 10.6 °, 13.6 °, 15.4 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ.
Embodiment I-43 the crystalline form of embodiment I-41 or I-42, characterized by an XRPD pattern substantially the same as the pattern shown in figure 13.
Embodiment I-44 the crystalline form of any one of embodiments I-41 to I-43, characterized by a TG thermogram substantially the same as the one set forth in fig. 14.
Embodiment I-45 the crystalline form of any one of embodiments I-41 to I-44, characterized by a DSC thermogram substantially the same as the one set forth in figure 15.
Embodiment I-46 the crystalline form of embodiment I-41, characterized by having at least two of the following:
an xrpd pattern comprising at least three peaks selected from 8.4 °, 10.6 °, 13.6 °, 15.4 ° and 18.8 ° 2 Θ ± 0.2 ° 2 Θ;
tg thermogram substantially the same as the pattern shown in fig. 14; and
a dsc thermogram substantially the same as the one set forth in figure 15.
Embodiment I-47.N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea in a crystalline form referred to as form VIII of Compound 1.
Embodiment I-48 the crystalline form of embodiment I-47, characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 7.4 °, 10.6 °, 13.7 °, 15.2 °, and 18.7 ° 2 Θ ± 0.2 ° 2 Θ.
Embodiment I-49. The crystalline form of embodiment I-47 or I-48, characterized by an XRPD pattern substantially the same as the pattern shown in figure 16.
Embodiment I-50 the crystalline form of any one of embodiments I-47 to I-49, characterized by a TG thermogram substantially the same as the one set forth in fig. 17.
Embodiment I-51 the crystalline form of any one of embodiments I-47 to I-50, characterized by a DSC thermogram substantially the same as the one set forth in figure 18.
Embodiments I-52 crystalline forms of embodiments I-47 characterized by having at least two of the following:
an xrpd pattern comprising at least three peaks selected from 7.4 °, 10.6 °, 13.7 °, 15.2 ° and 18.7 ° 2 Θ ± 0.2 ° 2 Θ;
the tg thermogram is substantially the same as the pattern shown in fig. 17; and
a dsc thermogram substantially the same as the one set forth in figure 18.
A crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, referred to as form IX of compound 1.
Embodiment I-54 the crystalline form of embodiment I-53, characterized by an XRPD pattern substantially the same as the pattern shown in figure 19.
Embodiment I-55. The crystalline form of embodiment I-53 or I-54, characterized by a TG thermogram substantially the same as the pattern shown in FIG. 20.
Embodiment I-56 the crystalline form of any one of embodiments I-53 to I-55, characterized by a DSC thermogram substantially the same as the one set forth in figure 21.
Embodiment I-57 the crystalline form of embodiment I-53 characterized by having at least two of the following:
the xrpd pattern is substantially the same as the pattern shown in figure 19;
tg thermogram substantially the same as the pattern shown in fig. 20; and
a dsc thermogram substantially the same as the one set forth in figure 21.
Embodiment I-58.A crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, which is designated form X of Compound 1.
Embodiment I-59 the crystalline form of embodiment I-58 characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 4.6 °, 9.1 °, 9.6 °, 17.4 °, and 18.8 ° 2 Θ ± 0.2 ° 2 Θ.
Embodiment I-60. The crystalline form of embodiment I-58 or I-59, characterized by an XRPD pattern substantially the same as the pattern shown in figure 22.
Embodiment I-61 the crystalline form of any one of embodiments I-58 to I-60, characterized by a TG thermogram substantially the same as the one set forth in fig. 23.
Embodiment I-62 the crystalline form of any one of embodiments I-58 to I-61, characterized by a DSC thermogram substantially the same as the one set forth in figure 24.
Embodiment I-63 the crystalline form of embodiment I-58, characterized by having at least two of the following:
an xrpd pattern comprising at least three peaks selected from 4.6 °, 9.1 °, 9.6 °, 17.4 ° and 18.8 ° 2 Θ ± 0.2 ° 2 Θ;
the tg thermogram is substantially the same as the pattern shown in fig. 23; and
a dsc thermogram substantially the same as the one set forth in figure 24.
Embodiment I-64.A crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, which is designated form XI of Compound 1.
Embodiment I-65 the crystalline form of embodiment I-64 characterized by an XRPD pattern substantially the same as the pattern shown in figure 30.
Embodiment I-66. The crystalline form of embodiment I-64 or I-65, characterized by a TG thermogram substantially the same as the pattern shown in the upper graph of FIG. 31.
Embodiment I-67 the crystalline form of any one of embodiments I-64 to I-66, characterized by a DSC thermogram substantially the same as the one set forth in the lower graph of FIG. 31.
Embodiment I-68 the crystalline form of embodiment I-64 characterized by having at least two of the following:
a) The XRPD pattern is substantially the same as the pattern shown in figure 30;
b) The TG thermogram is substantially the same as the pattern shown in the upper graph of fig. 31; and
c) The DSC thermogram is substantially the same as the one set forth in the lower panel of figure 31.
An embodiment of a crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, which is designated form XII of Compound 1.
Embodiment I-70. The crystalline form of embodiment I-69, characterized by an XRPD pattern substantially the same as the pattern shown in figure 32.
Embodiment I-71. The crystalline form of embodiment I-69 or I-70, characterized by a TG thermogram substantially the same as the pattern shown in the upper graph of FIG. 33.
Embodiment I-72 the crystalline form of any one of embodiments I-69 to I-71, characterized by a DSC thermogram substantially the same as the one set forth in the lower graph of FIG. 33.
Embodiment I-73 the crystalline form of embodiment I-69, characterized by having at least two of the following:
a) The XRPD pattern is substantially the same as the pattern shown in figure 32;
b) The TG thermogram was substantially the same as the pattern shown in the upper graph of fig. 33; and
c) The DSC thermogram is substantially the same as the one shown in the lower panel of figure 33.
Embodiment I-74A pharmaceutical composition comprising one or more of the crystalline forms of any one of embodiments I-1 to I-73 and a pharmaceutically acceptable carrier.
Embodiments I-75 the pharmaceutical composition of embodiments I-74 comprising a crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, referred to as form I of compound 1.
Embodiment I-76 a method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of one or more crystalline forms of any one of embodiments I-1 to I-73.
Embodiment I-77 the method of embodiment I-76 comprising administering to the subject an effective amount of a crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, form I referred to as Compound 1.
Embodiment I-78A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition of embodiment I-74 or I-75.
Embodiment I-79 the method of any one of embodiments I-76 to I-78, wherein the disorder is a hormone-dependent condition.
Embodiment I-80 the method of embodiment I-79, wherein the hormone-dependent condition is sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastases of sex hormone-dependent cancer, prostatic hypertrophy, uterine fibroids, adenomyomas, uterine fibroids, precocious puberty, menopause, premenstrual syndrome, dysmenorrhea, multifocal ovarian syndrome, polycystic ovarian syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, or menstrual bleeding.
Embodiment I-81 the method of embodiment I-79 or I-80, wherein the hormone dependent condition is prostate cancer, uterine cancer, breast cancer or ovarian cancer.
Embodiment I-82 the method of any one of embodiments I-79 to I-81, wherein the hormone dependent condition is prostate cancer.
Embodiment I-83 the method of any one of embodiments I-79 to I-81, wherein the hormone dependent condition is uterine cancer.
Embodiment I-84. The method of any one of embodiments I-79 to I-81, wherein the hormone dependent condition is breast cancer.
Embodiment I-85 the method of any one of embodiments I-79 to I-81, wherein the hormone dependent condition is ovarian cancer.
Embodiment I-86. The method of embodiment I-79 or I-80, wherein the hormone dependent condition is uterine leiomyoma.
Embodiments I-87, the method of embodiments I-79, wherein the hormone-dependent condition is menstrual bleedings associated with uterine leiomyoma.
Embodiment I-88 the method of embodiment I-79, wherein the hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma.
Embodiment I-89 the method of embodiment I-79 or I-80, wherein the hormone-dependent condition is endometriosis.
Embodiment I-90. The method of embodiment I-79 or I-80, wherein the hormone-dependent condition is adenomyosis.
Embodiment I-91 the method of embodiment I-79 or I-80, wherein the hormone dependent condition is menstrual bleeding.
The method of any one of embodiments I-76 to I-91, comprising administering to the subject estradiol or a corresponding amount of estradiol equivalent.
The method of any one of embodiments I-76 to I-91, comprising administering progesterone to the subject.
Embodiment I-93. The method of any one of embodiments I-76 to I-91 comprising administering to the subject estradiol or a corresponding amount of estradiol equivalent and progesterone.
Embodiment I-94. The method of embodiment I-92 or I-93, wherein said progestin is norethindrone acetate.
Embodiment I-95. One or more of the crystalline forms of any one of embodiments I-1 to I-73 for use in treating a disorder in a subject in need thereof.
Embodiment I-96 one or more crystalline forms for use of embodiment I-95 comprising a crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, referred to as form I of Compound 1, for use in treating a disorder in a subject in need thereof.
Embodiment I-97 one or more of the crystalline forms of embodiment I-95 or I-96 for use wherein the disorder is a hormone-dependent condition.
Embodiment I-98 the crystalline form or forms for use of embodiment I-97 wherein the hormone-dependent condition is sex hormone dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastases of sex hormone dependent cancer, prostatic hypertrophy, uterine fibroids, adenomyomas, uterine fibroids, precocious puberty, menopause, premenstrual syndrome, dysmenorrhea, multifocal ovarian syndrome, polycystic ovarian syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, or menstrual bleedings.
Embodiment I-99 one or more of the crystalline forms of embodiment I-97 or I-98 for use wherein the hormone dependent condition is prostate cancer, uterine cancer, breast cancer or ovarian cancer.
Embodiment I-100 one or more crystalline forms of any one of embodiments I-97 to I-99 for use wherein the hormone dependent condition is prostate cancer.
Embodiment I-101 one or more crystalline forms for use of any one of embodiments I-97 to I-99, wherein said hormone-dependent condition is uterine cancer.
Embodiment I-102 one or more crystalline forms of any one of embodiments I-97 to I-99 for use wherein the hormone dependent condition is breast cancer.
Embodiment I-103 one or more crystalline forms for use of any one of embodiments I-97 to I-99, wherein the hormone-dependent condition is ovarian cancer.
Embodiment I-104 one or more crystalline forms of embodiment I-97 or I-98 for use wherein the hormone dependent condition is uterine leiomyoma.
Embodiment I-105. The one or more crystalline forms for use of embodiment I-97, wherein said hormone-dependent condition is menstrual bleedings associated with uterine leiomyoma.
Embodiment I-106 the crystalline form or forms of embodiment I-97 for use, wherein said hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma.
Embodiment I-107 one or more of the crystalline forms for use of embodiment I-97 or I-98, wherein the hormone-dependent condition is endometriosis.
Embodiment I-108. One or more of the crystalline forms for use of embodiment I-97 or I-98, wherein the hormone-dependent condition is adenomyosis.
Embodiment I-109. One or more of the crystalline forms for use of embodiment I-97 or I-98, wherein the hormone-dependent condition is menstrual bleeding.
Embodiment I-110 the one or more crystalline forms for use of any one of embodiments I-95 to I-109, wherein the one or more crystalline forms for use are used in combination with estradiol or a corresponding amount of estradiol equivalent.
Embodiment I-111. The one or more crystalline forms for use of any one of embodiments I-95 to I-109, wherein the one or more crystalline forms for use are used in combination with a progestin.
Embodiment I-112 the one or more crystalline forms for use of any one of embodiments I-95 to I-109, wherein the one or more crystalline forms for use are used in combination with estradiol or a corresponding amount of estradiol equivalent or progesterone.
Embodiment I-113 one or more of the crystalline forms for use of embodiment I-111 or I-112, wherein the progestin is norethindrone acetate.
Embodiment I-114. The pharmaceutical composition of embodiment I-74 or I-75 for use in treating a disorder in a subject in need thereof.
Embodiment I-115 the pharmaceutical composition for use of embodiment I-114, wherein the disorder is a hormone-dependent condition.
Embodiment I-116 the pharmaceutical composition for use of embodiment I-115, wherein the hormone-dependent condition is sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastases of sex hormone-dependent cancer, prostatic hypertrophy, uterine fibroids, adenomyomas, uterine fibroids, precocious puberty, menopause, premenstrual syndrome, dysmenorrhea, multifocal ovarian syndrome, polycystic ovarian syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, or menstrual bleedings.
Embodiment I-117 the pharmaceutical composition for use of embodiment I-115 or I-116, wherein said hormone dependent condition is prostate cancer, uterine cancer, breast cancer or ovarian cancer.
The pharmaceutical composition for use of any one of embodiments I-115 to I-117, wherein said hormone dependent condition is prostate cancer.
Embodiment I-119. The pharmaceutical composition for use of any one of embodiments I-115 to I-117, wherein said hormone dependent condition is uterine cancer.
Embodiment I-120 the pharmaceutical composition for use of any one of embodiments I-115 to I-117, wherein said hormone dependent condition is breast cancer.
The pharmaceutical composition for use of any one of embodiments I-115 to I-117, wherein the hormone dependent condition is ovarian cancer.
Embodiment I-122 the pharmaceutical composition for use of embodiment I-115 or I-116, wherein the hormone dependent condition is uterine leiomyoma.
Embodiments I-123 the pharmaceutical composition for use of embodiments I-115, wherein the hormone-dependent condition is menstrual bleedings associated with uterine leiomyoma.
Embodiment I-124 the pharmaceutical composition for use of embodiment I-115, wherein the hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma.
Embodiment I-125 the pharmaceutical composition for use of embodiment I-115 or I-116, wherein the hormone-dependent condition is endometriosis.
Embodiment I-126 the pharmaceutical composition for use of embodiment I-115 or I-116, wherein said hormone dependent condition is adenomyosis.
Embodiment I-127 the pharmaceutical composition for use of embodiment I-115 or I-116, wherein the hormone dependent condition is menstrual bleeding.
Embodiment I-128 the pharmaceutical composition for use of any one of embodiments I-114 to I-127, wherein said pharmaceutical composition for use is used in combination with estradiol or a corresponding amount of estradiol equivalent.
Embodiment I-129 the pharmaceutical composition for use of any one of embodiments I-114 to I-127, wherein said pharmaceutical composition for use is used in combination with a progestin.
Embodiment I-130 the pharmaceutical composition for use of any one of embodiments I-114 to I-127, wherein said pharmaceutical composition for use is used in combination with estradiol or a corresponding amount of estradiol equivalent and progesterone.
Embodiment I-131, embodiment I-129 or I-130, wherein the progestin is norethindrone acetate.
Embodiment I-132. Use of one or more of the crystalline forms of any one of embodiments I-1 to I-73 for treating a disorder in a subject in need thereof.
Embodiment I-133 the use of embodiment I-132 comprising using a crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, referred to as form I of compound 1, to treat a disorder in a subject in need thereof.
Embodiment I-134 the use of a pharmaceutical composition of embodiment I-74 or I-75 for treating a disorder in a subject in need thereof.
Embodiment I-135 use of one or more crystalline forms of any one of embodiments I-1 to I-73 for the manufacture of a medicament for the treatment of a disorder.
Embodiment I-136 the use of embodiment I-135, comprising the use of a crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, form I, designated compound 1, in the manufacture of a medicament for the treatment of a disorder.
Embodiment I-137 the use of a pharmaceutical composition of embodiment I-74 or I-75 in the manufacture of a medicament for the treatment of a disorder.
Embodiment I-138. Use of one or more of the crystalline forms of any one of embodiments I-1 to I-73 as a medicament for the treatment of a disorder.
Embodiment I-139. Use of embodiment I-138 comprising the use of a crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, form I, referred to as compound 1, as a medicament for the treatment of a disorder.
Embodiment I-140. The pharmaceutical composition of embodiment I-74 or I-75 for use as a medicament for the treatment of a disorder.
Embodiment I-141 use according to any one of embodiments I-132 to I-140, wherein the disorder is a hormone-dependent condition.
Embodiment I-142 the use of embodiment I-141 wherein the hormone-dependent condition is sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastases of sex hormone-dependent cancer, prostatic hypertrophy, uterine fibroids, adenomyomas, uterine fibroids, precocious puberty, menopause, premenstrual syndrome, dysmenorrhea, multifocal ovarian syndrome, polycystic ovarian syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, or menstrual bleedings.
Embodiment I-143 the use of embodiment I-141 or I-142, wherein said hormone dependent condition is prostate cancer, uterine cancer, breast cancer or ovarian cancer.
Embodiment I-144 the use of any one of embodiments I-141 to I-143 wherein said hormone dependent condition is prostate cancer.
Embodiment I-145 the use of any one of embodiments I-141 to I-143, wherein said hormone dependent condition is uterine cancer.
Embodiment I-146 the use of any one of embodiments I-141 to I-143, wherein said hormone dependent condition is breast cancer.
Embodiment I-147 the use of any one of embodiments I-141 to I-143, wherein said hormone dependent condition is ovarian cancer.
Embodiment I-148 use of embodiment I-141 or I-142 wherein said hormone dependent condition is uterine leiomyoma.
Embodiment I-149 use of embodiment I-141, wherein the hormone dependent condition is menstrual bleeding associated with uterine leiomyoma.
Embodiment I-150 the use of embodiment I-141, wherein said hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma.
Embodiment I-151 the use of embodiment I-141 or I-142 wherein the hormone dependent condition is endometriosis.
Embodiment I-152 the use of embodiment I-141 or I-142 wherein the hormone dependent condition is adenomyosis.
Embodiment I-153 the use of embodiment I-141 or I-142, wherein the hormone dependent condition is menstrual bleeding.
Embodiment I-154. The use of any one of embodiments I-132 to I-153, which comprises treating a condition with estradiol or a corresponding amount of estradiol equivalent.
Embodiment I-155 the use of any one of embodiments I-132 to I-153, comprising the use of progesterone to treat a disorder.
Embodiment I-156 the use of any one of embodiments I-132 to I-153, which comprises treating a condition with estradiol or a corresponding amount of an estradiol equivalent and progesterone.
Embodiment I-157. Use of embodiment I-155 or I-156 wherein the progestin is norethindrone acetate.
Embodiment I-158 a process for preparing the crystalline form of any one of embodiments I-1 to I-15, the process comprising:
a) Dissolving a crystalline form of form I N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, referred to as compound 1, in a mixture of DMF and acetone (about 6, 94, v/v) at about 25 ℃ to form a solution;
b) Stirring the solution at a temperature of about-15 ℃ to about-25 ℃ for about 3 days to produce a suspension; and
c) Separating the solid from the suspension by vacuum filtration to provide the crystalline form of any one of embodiments I-1 to I-15.
Embodiment I-159 the process of embodiment I-158 comprising vacuum drying the isolated solid at about 60 ℃ for about 4 hours to provide the crystalline form of any one of embodiments I-1 to I-15.
Examples
General methods of the examples
All solvents (HPLC or reagent grade) or reagents used in the examples were supplied by Wako Pure Chemical Industries.
X-ray powder diffraction (XRPD)
X-ray powder diffractograms were obtained using D8 DISCOVER (Bruker AXS Corporation) and a Ultima IV 3kW X-ray diffractometer (Rigaku Corporation). The samples were placed on a glass plate or a silicon sample plate. The instrument parameters were as follows:
d8 DISCOVER:40kV/50mA; vantec 2-dimensional detector: detection angle range (2 θ) 4-28 °, ultima IV: cu ka source (λ =0.154 nm) radiation, 40kV/50mA; a scanning speed (2 θ); the detection angle range (2 theta) of 6 DEG/minute is 2-35 deg.
Gas Chromatography (GC)
The solvent content in the samples was measured using GC 2010Plus (Shimadzu Corporation). The sample was dissolved in a vial containing acetone. The analysis conditions and calculation formula of the solvent content are as follows:
karl Fischer (KF) titration
The water content in the samples was measured using Hiranuma aquacounter AQ-7 (Hiranuma Corporation). The samples were dissolved in Aqualite RS-A and the water content was measured by Coulometric titration.
Differential Scanning Calorimeter (DSC)
All studies used a differential scanning calorimeter of Hitachi DSC7000X (Hitachi High-Tech Science Corporation). The sample was placed in a coiled aluminum DSC pan and heated from 25 ℃ to 300 ℃ at a rate of 5 ℃/min under a nitrogen flow atmosphere of 30 mL/min. DSC analyses of form II of compound 1, form III of compound 1, form V of compound 1, form VI of compound 1, form VII of compound 1, form VIII of compound 1, form IX of compound 1, and form X of compound 1 were performed using this method.
Thermogravimetric analysis (TG)
For thermogravimetric studies, hitachi STA7200 (Hitachi High-Tech Science Corporation) was used to determine the percent weight loss upon heating. The sample was placed in an open aluminum pan and the furnace was heated from 25 ℃ to 300 ℃ at a rate of 5 ℃/min under a nitrogen flow atmosphere of 200 mL/min. This method was used to perform TG analysis of form II of compound 1, form III of compound 1, form V of compound 1, form VI of compound 1, form VII of compound 1, form VIII of compound 1, form IX of compound 1 and form X of compound 1.
TGA-DSC
DSC/TGA analysis was performed using a Mettler-Toledo TGA/DSC3+ analyzer. Temperature calibration was performed using calcium oxalate, indium, tin and zinc. The sample was placed in an aluminum pan. The sample was sealed, the cap punctured and then inserted into the TG oven. The sample was sealed, the lid pierced, then inserted into a TG oven, and the oven was heated from 25 ℃ to 350 ℃ at a rate of 10 ℃/min under a nitrogen flow atmosphere of 50 mL/min. TGA-DSC analyses of form XI of compound 1 and form XII of compound XII were performed using this method. The term "about" when used in conjunction with TGA or DSC values means a range of ± 2 ℃.
High Performance Liquid Chromatography (HPLC)
The content of the substance in the test solution was measured using an HPLC Prominence/PDA detector (Shimadzu Corporation). The analysis conditions and calculation formula are as follows:
preparation and characterization of a crystalline form of Compound 1
Amorphous form of Compound 1
The present disclosure provides a process for preparing an amorphous form of compound 1. Form I of compound 1 was dissolved in dimethyl sulfoxide and 1,4-dioxane at a ratio (v/v) of about 1. Dimethyl sulfoxide and 1,4-dioxane were then evaporated by vacuum freeze drying to provide the amorphous powder form of compound 1. Amorphous forms of compound 1 can be prepared using compound 1 prepared as described in U.S. patent No. 7,300,935, U.S. patent No. 8,058,280, U.S. patent No. 8,735,401, and U.S. patent No. 9,346,822, which are incorporated herein by reference in their entirety.
Form I of Compound 1
The present disclosure provides a process for preparing form I of compound 1. Form I of compound 1 can be prepared by dissolving form V of compound 1 in DMSO at a temperature of about 35 ℃ +/-5 ℃. Ethanol was then added to the mixture. The mixture was then filtered while maintaining the temperature of the mixture at about 35 ℃ +/-5 ℃ and the solids were washed with ethanol, and the mixture was stirred at about 35 ℃ +/-5 ℃ for about one hour, cooled to about 25 ℃ +/-5 ℃ and stirred for about 12 hours or more. The resulting precipitate provided form I of compound 1.
Form II of Compound 1
The present disclosure provides several methods for preparing form II of compound 1.
The method comprises the following steps: about 0.3mL of a DMF solution of form I of Compound 1 was added to 5mL of acetone at room temperature (DMF: acetone, 6. When a white suspension consisting of fibers was observed, the mixture was stirred at a temperature of about-15 ℃ to about-25 ℃ for about 3 days. The solid was isolated by vacuum filtration and dried under vacuum at about 60 ℃ for about 4 hours to give compound 1, form II.
The method 2 comprises the following steps: about 1g of form I of compound 1 was dissolved in 2.6mL of a mixture of 80 DMF: acetone at about 40 ℃. Acetone at room temperature was added to the mixture to achieve a DMF to acetone ratio of about 12.5 v/v. The mixture is then seeded with about 0.5% by weight of form II crystals. The mixture was placed in a freezer overnight at about-15 ℃ to about-25 ℃, after which the resulting suspension was vacuum filtered, the wet cake was washed with cold acetone, and vacuum dried at about 62 ℃ to about 65 ℃ for about 5 hours. The solid is in accordance with form II of compound 1; the yield thereof was found to be 78.5%.
The method 3 comprises the following steps: about 1g of Compound 1, form 1, was dissolved in 2.2mL of DMF at about 40 ℃. Acetone at room temperature was added to the mixture to achieve a DMF to acetone ratio of about 10. The mixture was then inoculated with about 0.5% by weight of form II. The mixture was placed in a freezer overnight at about-15 ℃ to about-25 ℃, after which the resulting suspension was vacuum filtered, the wet cake was washed with cold acetone, and vacuum dried at about 62 ℃ to about 65 ℃ for about 5 hours. The solid is in accordance with form II of compound 1; the yield thereof was found to be 77.5%.
Form III of Compound 1
The present disclosure provides a process for preparing form III of compound 1. Form I of Compound 1 is dissolved in DMF and then precipitated with water at about-10 deg.C (DMF: H)2O42). The mixture was then inoculated with form II and the resulting slurry was stored at about-10 ℃ for three days, at which time a thick white flowing suspension was observed. The solid was consistent with form III as determined by XRPD.
Form IV of Compound 1
The present disclosure provides a process for preparing form IV of compound 1. Form III of compound I is converted to anhydrate form IV by heating form III to between about 79 ℃ and about 197 ℃.
Form V of Compound 1
The present disclosure provides a process for preparing form V of compound 1. The amorphous form of compound 1 was dissolved in toluene at about 55 ℃ to make a solution of about 10 mg/mL. Toluene was then evaporated at about 55 ℃ by a stream of nitrogen to provide compound 1 as powder form V.
Form VI of Compound 1
The present disclosure provides a process for preparing form VI of compound 1. The amorphous form of compound 1 was dissolved in anisole at about 55 ℃ to make a solution of about 10 mg/mL. Approximately equal volumes of heptane were added to the anisole solution at about 55 deg.C to produce a solution of about 5 mg/mL. Anisole and heptane were then evaporated at about 55 deg.c by a stream of nitrogen to provide compound 1 in powder form VI.
Form VII of Compound 1
The present disclosure provides a process for preparing form VII of compound 1. The amorphous form of compound 1 was dissolved in 2-propanol at about 55 ℃ to make a solution of about 10 mg/mL. About 2.5 volumes of water were added to the 2-propanol solution at about 55 deg.C to make a solution of about 2.9 mg/mL. The solution was cooled from about 55 c to about 10 c at a rate of about 3 c/hour with stirring at about 500 rpm. The crystalline solid in suspension was collected by vacuum filtration using a filter (Millipore JGWP 0.2 μm) to provide compound 1 as powder form VII.
Form VIII of Compound 1
The present disclosure provides a process for preparing form VIII of compound 1. Form I of compound 1 was dispersed into a mixture of 1,4-dioxane and water (about 1, v/v) to make a slurry state with a concentration of about 20 mg/mL. The slurry was aged by stirring at about 25 ℃ for about three days. The dispersed powder was collected by vacuum filtration using a filter (Millipore JGWP 0.2 μm) to provide compound 1 in powder form VIII.
Form IX of Compound 1
The present disclosure provides a process for preparing form IX of compound 1. The amorphous form of compound 1 was dissolved in α, α, α -trifluorotoluene at about 55 ℃ to make a solution of about 10 mg/mL. To the α, α, α -trifluorotoluene solution was added about equal volumes of heptane at about 55 ℃ to make a solution of about 5 mg/mL. The α, α, α -trifluorotoluene and heptane were then evaporated by a nitrogen stream at about 55 ℃ to provide compound 1 in powder form IX.
Form X of Compound 1
The present disclosure provides a process for preparing form X of compound 1. The amorphous form of compound 1 was dissolved in trifluoroethanol at about 55 ℃ to make a solution of about 200 mg/mL. About equal volumes of diisopropyl ether were added to the trifluoroethanol solution at about 55 ℃ to make a solution of about 100 mg/mL. The solution was cooled from about 55 ℃ to about 10 ℃ at a rate of about 3 ℃ per hour with stirring at about 500 rpm. The crystalline solid in suspension was collected by vacuum filtration using a filter (Millipore JGWP 0.2 μm) to provide compound 1 as powder form X.
Form XI of Compound 1
The present disclosure provides several methods for preparing form XI of compound 1.
The method comprises the following steps: form I of compound 1 (-100 mg) was dissolved in 0.5mL of DMF at ambient temperature. The resulting clear solution was cooled to about-10 ℃ and no precipitate was observed. An aliquot of methyl tert-butyl ether (MTBE) was added to achieve a DMF to MTBE volume ratio of 50 and seeds of form II of compound 1 were added to give a cloudy solution. An additional amount of MTBE was added to achieve a DMF to MTBE volume ratio of 25. The cloudy solution was stirred at about-10 ℃ overnight, resulting in a white flowing suspension. After stirring at about-10 ℃ for a total of about 4 days, the solid was isolated by vacuum filtration cold using a funnel adapted on dry ice and washed with cold MTBE adapted in a freezer at about-15 ℃ to about-25 ℃ to provide form XI of compound 1.
The method 2 comprises the following steps: form I of compound 1 (-100 mg) was dissolved in 0.5mL of DMF at ambient temperature. The resulting clear solution was cooled to about-10 ℃ and no precipitation was observed. An aliquot of isopropanol was added to achieve a DMF to isopropanol volume ratio of 50 and seeds of form II of compound 1 were added to give a cloudy solution. The cloudy solution became a thin suspension in half an hour and was allowed to stir overnight at about-10 ℃ to yield a white, slightly dense, flowing suspension. After stirring at about-10 ℃ for a total of about 4 days, the solid of the resulting milky thick suspension was diluted with 0.5mL of cold isopropanol adapted in a freezer at about-15 ℃ to about-25 ℃ and cold separated by vacuum filtration using a funnel adapted on dry ice to provide form XI of compound 1.
Form XII of Compound 1
The present disclosure provides a process for preparing form XII of compound 1.
The method comprises the following steps: form I of compound 1 (-100 mg) was dissolved in 0.3mL of DMF at ambient temperature. The resulting clear solution was added dropwise to 5.0mL of acetone with stirring without causing precipitation. The DMF to acetone volume ratio was calculated as 6. The clear solution was allowed to stir at about-15 ℃ to about-25 ℃ for about 2 days, and the resulting cloudy solution was stirred for an additional 1 day, resulting in a white suspension. The solid was cold isolated by vacuum filtration using a funnel adapted on dry ice to provide form XII of compound 1.
The method 2 comprises the following steps: form I of Compound 1 (. About.1.0 g) was slurried in 2.0mL of 80 (v/v) DMF: acetone at about 40 ℃. Additional aliquots of DMF were added until complete dissolution was observed, reaching a DMF to acetone ratio of 85 (v/v). The resulting clear solution was placed on a stirrer at ambient temperature and acetone was added slowly to achieve a DMF: acetone ratio of 12.5. The clear solution was seeded with 0.45 wt% form II of compound 1 and the resulting cloudy solution was placed in a freezer overnight at about-15 ℃ to about-25 ℃. Solids were isolated by vacuum filtration using a suitable funnel in a freezer at about-15 ℃ to about-25 ℃. The solid is washed with cold acetone, also conditioned in a freezer at about-15 ℃ to about-25 ℃, to provide form XII of compound 1.
The method 3 comprises the following steps: form I of Compound 1 (. About.1.0 g) was slurried in 1.0mL of DMF at about 40 ℃. A total of 1.2mL of additional aliquots of DMF were added until complete dissolution was observed. The resulting clear solution was placed on a stirrer at ambient temperature and acetone was added slowly to achieve a DMF to acetone ratio of 11. The clear solution was seeded with 0.5 wt% form II of compound 1, resulting in a cloudy solution. Additional acetone (1 mL) was added to achieve a DMF to acetone ratio of 10 (v/v) and the sample was allowed to stir at ambient temperature, resulting in a white suspension that was placed in a freezer overnight at about-15 ℃ to about-25 ℃. The solid was isolated by cold filtration under vacuum and washed with cold acetone to afford form XII of compound 1. Both the acetone and funnel were conditioned in a freezer at about-15 ℃ to about-25 ℃ prior to use.
XRPD characterization of the crystalline form of compound 1
XRPD data was collected as detailed above for the crystalline form of compound 1 disclosed herein. The XRPD patterns of these crystalline forms are detailed in figure 1 (form II of compound 1), figure 4 (form III of compound 1), figure 7 (form V of compound 1), figure 10 (form VI of compound 1), figure 13 (form VII of compound 1), figure 16 (form VIII of compound 1), figure 19 (form IX of compound 1), figure 22 (form X of compound 1), figure 30 (form XI of compound 1) and figure 32 (form XII of compound 1). The peaks present in these XRPD patterns are listed in table 2 above. All peaks are tabulated at an angle 2 theta + -0.2 deg. 2 theta.
Figure 25 depicts the powder X-ray diffraction pattern of form I of compound 1. Figure 26 depicts a powder X-ray diffraction pattern of crystals of tetrahydrofuran solvate of compound 1.
GC characterization of the crystalline form of Compound 1
The GC results of the crystallization solvents present in form V-X are shown in the table below:
solvent content of form V-X
The amount of solvent detected by GC indicates that form V-X is a hemisolvate or monosolvate of compound 1.
Karl Fischer (KF) titration of form III
The water content in hemihydrate form a was 1.3%, as determined by KF titration, which corresponds to hemihydrate.
Thermal analysis (DSC and TG)
DSC and TG data were collected for the crystalline forms of compound 1 disclosed herein as detailed above. The TG thermograms of these crystalline forms are detailed in fig. 2 (form II of compound 1), fig. 5 (form III of compound 1), fig. 8 (form V of compound 1), fig. 11 (form VI of compound 1), fig. 14 (form VII of compound 1), fig. 17 (form VIII of compound 1), fig. 20 (form IX of compound 1), fig. 23 (form X of compound 1), fig. 31 (upper panel, form XI of compound 1), and fig. 33 (upper panel, form XII of compound 1). The DSC thermograms of these crystalline forms are detailed in fig. 3 (form II of compound 1), fig. 6 (form III of compound 1), fig. 9 (form V of compound 1), fig. 12 (form VI of compound 1), fig. 15 (form VII of compound 1), fig. 18 (form VIII of compound 1), fig. 21 (form IX of compound 1), fig. 24 (form X of compound 1), fig. 31 (lower panel, form XI of compound 1), and fig. 33 (lower panel, form XII of compound 1). Thermal events in DSC and TG of the crystalline form of compound 1 are detailed in the table below.
Thermal events in DSC and TG of form II
Thermal events | T (Start, DEG C) | T (Peak top, DEG C) |
Melting Point (degradation) | (180) | (187) |
Degradation of the polymer | 175 | 208 |
Exothermic heat of degradation | - | 192 |
Thermal events in DSC and TG of form III
Thermal events in DSC and TG of form V
Thermal events | T (Start, DEG C) | T (Peak, DEG C) |
Volatilization of minute residual solvent | 36 | 39,66 |
Desolvation of | - | 163 |
Melting Point (degradation) | (145) | (153) |
Degradation of | 163 | 202 |
Exothermic heat of degradation | - | 198 |
Thermal events in DSC and TG of form VI
Thermal event | T (Start, deg.C) | T (Peak, DEG C) |
Volatilization of minute residual solvent | - | 66 |
Desolvation of | - | 158 |
Melting Point (degradation) | (143) | (147) |
Degradation of | 158 | 201 |
Exothermic heat of degradation | - | 155,198 |
Thermal events in DSC and TG of form VII
Thermal event | T (Start, DEG C) | T (Peak top, DEG C) |
Volatilization of minute residual solvent | - | 92,122 |
Desolvation of | - | 161 |
Melting Point (degradation) | (136) | (147) |
Degradation of the polymer | 161 | 205 |
Exothermic heat of degradation | - | 179 |
Thermal events in DSC and TG of form VIII
Thermal events in DSC and TG of form IX
Thermal event | T (Start, deg.C) | T (Peak top, DEG C) |
Volatilization of minute residual solvent | - | 104,133 |
Melting Point (degradation) | (135) | (156) |
Degradation of | - | 157 |
Exothermic heat of degradation | - | 182 |
Thermal events in DSC and TG of form X
Thermal events | T (Start, DEG C) | T (Peak top, DEG C) |
Volatilization of minute residual solvent | - | 82 |
Desolvation of | - | 159 |
Melting Point (degradation) | (124) | (142) |
Degradation of | 159 | 197 |
Exothermic heat of degradation | - | 190 |
Thermal events in DSC and TG of form XI
Thermal events in DSC and TG of form XII
Solubility determination of form I and form II of Compound 1
The thermodynamic solubilities of form I and form II were determined at pH 1.2 and pH 6.8 and in 20mM GCDC (pH 6.8) at 37 ℃ with equilibration times of 2,6 and 24 hours. The average values of solubility (n = 3) are summarized in tables 3 and 4 above. Form I showed lower solubility than form II at pH 6.8 and in 20mM GCDC (pH 6.8), while all crystal forms were very soluble at pH 1.2.
Claims (17)
- A crystalline form of 1.N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, which is referred to as form II of compound 1.
- 2. The crystalline form of claim 1, characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ.
- 3. The crystalline form of claim 1, characterized by an X-ray powder diffraction pattern comprising at least five peaks selected from 7.2 °, 9.7 °, 10.7 °, 13.1 °, 15.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ.
- 4. The crystalline form of claim 1, characterized by an X-ray powder diffraction pattern comprising peaks at 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ.
- 5. The crystalline form of claim 4, wherein the X-ray powder diffraction pattern comprises one or more peaks selected from 7.2 °, 13.1 °, and 15.7 ° ± 0.2 ° 2 θ.
- 6. The crystalline form of any one of claims 1-5, characterized by an XRPD pattern substantially the same as the pattern shown in figure 1.
- 7. The crystalline form of any one of claims 1-6, characterized by beginning degradation between about 174 ℃ to about 176 ℃.
- 8. The crystalline form of any one of claims 1-7, characterized by beginning degradation at about 175 ℃.
- 9. The crystalline form of any one of claims 1-8, characterized by a thermogravimetric analysis (TG) thermogram substantially the same as the pattern shown in figure 2.
- 10. The crystalline form of any one of claims 1-9, characterized by an onset of melting between about 179 ℃ to about 181 ℃.
- 11. The crystalline form of any one of claims 1-10, characterized by beginning to melt at about 180 ℃.
- 12. The crystalline form of any of claims 1-11, characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an exothermic peak between about 191 ℃ to about 194 ℃.
- 13. The crystalline form of any one of claims 1-12, characterized by a DSC thermogram comprising an exothermic peak at about 192 ℃.
- 14. The crystalline form of any one of claims 1-13, characterized by a DSC thermogram substantially the same as the one set forth in figure 3.
- 15. The crystalline form of claim 1, characterized by having at least two of:a) The XRPD pattern comprises at least three peaks selected from 9.7 °, 10.7 °, 19.0 °, 19.3 °, and 20.9 ° 2 Θ ± 0.2 ° 2 Θ;b) Degradation started at about 175 ℃ as measured by TG; andc) As measured by DSC, has an exothermic peak at about 192 ℃.
- 16. A pharmaceutical composition comprising the crystalline form of any one of claims 1-15 and a pharmaceutically acceptable carrier.
- 17. A process for preparing the crystalline form of any one of claims 1-15, the process comprising:a) Dissolving a crystalline form of N- (4- (1- (2,6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea, form I referred to as compound 1, in a mixture of DMF and acetone (about 6, 94, v/v) at about 25 ℃ to form a solution;b) Stirring the solution at a temperature of about-15 ℃ to about-25 ℃ for about 3 days to produce a suspension; andc) Separating a solid from the suspension by vacuum filtration to provide the crystalline form of any one of claims 1-15.
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WO2022214645A1 (en) | 2021-04-09 | 2022-10-13 | Farmhispania Group, S.L. | Processes and intermediates for the preparation of relugolix |
WO2023066941A1 (en) | 2021-10-18 | 2023-04-27 | Myovant Sciences Gmbh | Crystalline form of an ethanol solvate of n-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-n'-methoxyurea |
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